Materials and methods for the treatment of gastroesophageal reflux disease

ABSTRACT

The subject invention provides novel compounds and compositions for the safe and effective treatment of gastroesophageal reflux and related conditions. In a preferred embodiment, the compositions of the subject invention comprise esterified cisapride derivatives. These compositions possess potent activity in treating gastroesophageal reflux disease and substantially reduce adverse effects associated with the administration of cisapride. These adverse effects include, but are not limited to, diarrhea, abdominal cramping and elevations of blood pressure and heart rate.

CROSS-REFERENCE TO RELATED APPLICATION

The subject application claims priority to provisional application U.S.Ser. No. 60/209,926, filed Jun. 7, 2000.

BACKGROUND OF INVENTION

Cisapride is one of a class of compounds known as benzamide derivatives,the parent compound of which is metoclopramide. U.S. Pat. Nos. 4,962,115and 5,057,525 (collectively “Van Daele” and incorporated by reference intheir entireties) disclose N-(3-hydroxy-4-piperidenyl) benzamides ofcisapride. Van Daele discloses that these compounds, thepharmaceutically acceptable acid addition salts thereof and thestereochemically isomeric forms thereof, stimulate the motility of thegastrointestinal system.

As a class, these benzamide derivatives have several prominentpharmacological actions. The prominent pharmacological activities of thebenzamide derivatives are due to their effects on the neuronal systemswhich are modulated by the neurotransmitter serotonin. The role ofserotonin, and thus the pharmacology of the benzamide derivatives, hasbeen broadly implicated in a variety of conditions for many years. Thus,research has focused on locating the production and storage sites ofserotonin as well as the location of serotonin receptors in the humanbody in order to determine the connection between these sites andvarious disease states or conditions.

In this regard, it was discovered that a major site of production andstorage of serotonin is the enterochromaffin cell of thegastrointestinal mucosa. It was also discovered that serotonin has apowerful stimulating action on intestinal motility by stimulatingintestinal smooth muscle, speeding intestinal transit, and decreasingabsorption time, as in diarrhea. This stimulating action is alsoassociated with nausea and vomiting.

Because of their modulation of the serotonin neuronal system in thegastrointestinal tract, many of the benzamide derivatives are effectiveanti-emetic agents and are commonly used to control vomiting duringcancer chemotherapy or radiotherapy, especially when highly emetogeniccompounds such as cisplatin are used. This action is almost certainlythe result of the ability of the compounds to block the actions ofserotonin (5HT) at specific sites of action, called the 5HT3-receptor,which was classically designated in the scientific literature as theserotonin M-receptor. Chemotherapy and radiation therapy may inducenausea and vomiting by the release of serotonin from damagedenterochromaffin cells in the gastrointestinal tract. Release of theneurotransmitter serotonin stimulates both afferent vagal nerve fibers(thus initiating the vomiting reflex) and serotonin receptors in thechemoreceptor trigger zone of the area postrema region of the brain. Theanatomical site for this action of the benzamide derivatives, andwhether such action is central (CNS), peripheral, or a combinationthereof, remains unresolved (Barnes et al., J. Pharm. Pharmacol. 40:586-588, 1988). Cisapride, like the other benzamide derivatives wouldappear to be an effective anti-emetic agent based on its ability tomodulate the activity of serotonin at the 5HT3 receptor.

A second prominent action of the benzamide derivatives is in augmentinggastrointestinal smooth muscle activity from the esophagus through theproximal small bowel, thus accelerating esophageal and small intestinaltransit as well as facilitating gastric emptying and increasing loweresophageal sphincter tone (Decktor et al., Eur. J. Pharmacol. 147:313-316, 1988). Although the benzamide derivatives are not cholinergicreceptor agonists per se, the aforementioned smooth muscle effects maybe blocked by muscarinic receptor blocking agents such as atropine orneuronal transmission inhibitors of the tetrodotoxin type which affectsodium channels. Similar blocking activity has been reported for thecontractile effects of serotonin in the small intestine. It is currentlybelieved that the primary smooth muscle effects of the benzamidederivatives are the result of an agonist action upon a new class ofserotonin receptors referred to as 5HT4 receptors which are located oninterneurons in the myenteric plexus of the gut wall. Activation ofthese receptors subsequently enhances the release of acetylcholine fromparasympathetic nerve terminals located near surrounding smooth musclefibers, and it is the combination of acetylcholine with its receptors onsmooth muscle membranes which is the actual trigger for musclecontraction.

Cisapride is presently used primarily to treat gastroesophageal refluxdisease. This disease is characterized as the backward flow of thestomach contents into the esophagus. One of the most important factorsin the pathogenesis of gastroesophageal reflux disease is a reduction inthe pressure barrier due to the failure of the lower esophagealsphincter. Failure of the lower esophageal sphincter can arise due to alow basal pressure, sphincter relaxation, or to a non-compensatedincrease in intragastric pressure. Other factors in the pathogenesis ofthe disease are delayed gastric emptying, insufficient esophagealclearing due to impaired peristalsis and the corrosive nature of thereflux material which can damage esophageal mucosa. Cisapride is thoughtto strengthen the anti-reflux barrier and improve esophageal clearanceby increasing the lower esophageal sphincter pressure and enhancingperistaltic contractions.

Because of its activity as a prokinetic agent, cisapride would alsoappear to be useful to treat dyspepsia, gastroparesis, constipation,post-operative ileus, and intestinal pseudo-obstruction. Dyspepsia is acondition characterized by an impairment of the power or function ofdigestion that can arise as a symptom of a primary gastrointestinaldysfunction or as a complication due to other disorders such asappendicitis, gallbladder disturbances, or malnutrition. Gastroparesisis a paralysis of the stomach brought about by a motor abnormality inthe stomach or as a complication of diseases such as diabetes,progressive systemic sclerosis, anorexia nervosa or myotonic dystrophy.Constipation is a condition characterized by infrequent or difficultevacuation of feces resulting from conditions such as lack of intestinalmuscle tone or intestinal spasticity. Post-operative ileus is anobstruction in the intestine due to a disruption in muscle tonefollowing surgery. Intestinal pseudo-obstruction is a conditioncharacterized by constipation, colicky pain, and vomiting, but withoutevidence of physical obstruction.

Drug toxicity is an important consideration in the treatment of humansand animals. Toxic side effects (adverse effects) resulting from theadministration of drugs include a variety of conditions which range fromlow grade fever to death. Drug therapy is justified only when thebenefits of the treatment protocol outweigh the potential risksassociated with the treatment. The factors balanced by the practitionerinclude the qualitative and quantitative impact of the drug to be usedas well as the resulting outcome if the drug is not provided to theindividual. Other factors considered include the physical condition ofthe patient, the disease stage and its history of progression, and anyknown adverse effects associated with a drug.

Drug elimination is typically the result of metabolic activity upon thedrug and the subsequent excretion of the drug from the body. Metabolicactivity can take place within the vascular supply and/or withincellular compartments or organs. The liver is a principal site of drugmetabolism. The metabolic process can be categorized into synthetic andnonsynthetic reactions. In nonsynthetic reactions, the drug ischemically altered by oxidation, reduction, hydrolysis, or anycombination of the aforementioned processes. These processes arecollectively referred to as Phase I reactions.

In Phase II reactions, also known as synthetic reactions orconjugations, the parent drug, or intermediate metabolites thereof, arecombined with endogenous substrates to yield an addition or conjugationproduct. Metabolites formed in synthetic reactions are, typically, morepolar and biologically inactive. As a result, these metabolites are moreeasily excreted via the kidneys (in urine) or the liver (in bile).Synthetic reactions include glucuronidation, amino acid conjugation,acetylation, sulfoconjugation, and methylation.

More than 90% of a dose of cisapride is metabolized by oxidativeN-dealkylation at the piperidine nitrogen or by aromatic hydroxylationoccurring on either the 4-fluorophenoxy or benzamide rings.

The administration of cisapride to a human has been found to causeadverse effects including, CNS disorders, increased systolic pressure,interactions with other drugs, diarrhea, and abdominal cramping.Further, it has been reported that intravenous administration ofcisapride demonstrates the occurrence of additional adverse (side)effects not experienced after oral administration of cisapride (Stacheret al. [1987] Digestive Diseases and Sciences 32(11):1223-1230). It isbelieved that these side effects are caused by the metabolites whichresult from the oxidative dealkylation or aromatic hydroxylation of thecompound which occurs in the cytochrome P-450 detoxification system.

Between July 1993 and December 1999, cisapride (PROPULSID, JanssenPharmaceutica Products, L.P.) has been reportedly associated with atleast 341 serious cardiac arrhythmias. These arrhythmias includeventricular tachycardia, ventricular fibrillation, torsades de pointes,and QT prolongation. Eighty (80) deaths have been reported. As a resultof these adverse effects, the product is being voluntarily withdrawnfrom the open market (in the United States) on Jul. 14, 2000; however,the drug will be available through an investigational limited accessprogram.

Thus, it would be particularly desirable to provide compounds with thetherapeutic advantages of cisapride which would not have theaforementioned disadvantages.

BRIEF SUMMARY

The subject invention provides novel compounds and compositions for thesafe and effective treatment of gastroesophageal reflux and relatedconditions. In a preferred embodiment, the compositions of the subjectinvention comprise esterified cisapride derivatives. These compositionspossess potent activity in treating gastroesophageal reflux disease andsubstantially reduce adverse effects associated with the administrationof cisapride. These adverse effects include, but are not limited to,diarrhea, abdominal cramping and elevations of blood pressure and heartrate.

Additionally, the novel compositions of the subject invention are usefulin treating emesis and other conditions, including but not limited todyspepsia, gastroparesis, constipation, and intestinalpseudo-obstruction. As an added benefit, adverse effects associated withthe administration of cisapride are also reduced in these methods oftreatment.

Advantageously, the subject invention provides compounds which arereadily metabolized by the physiological metabolic drug detoxificationsystems. Specifically, in a preferred embodiment, the therapeuticcompounds of the subject invention contain a moiety, which does notdetract from the ability of these compounds to provide a therapeuticbenefit, but which makes these compounds more susceptible to degradationby hydrolases. Specifically exemplified are compounds which contain anester group making them susceptible to degradation by serum and/orcytosolic esterases, thereby avoiding the cytochrome P-450 drugdetoxification system associated with adverse effects caused bycisapride and reducing the incidence of adverse events.

The subject invention further provides methods of treatment comprisingthe administration of these compounds to individuals in need oftreatment for gastroesophageal reflux disease and related conditions.

Advantageously, the therapeutic compounds of the subject invention arestable in storage and provide for safer metabolism of the drugs ascompared to other drugs which are available for treatment ofgastroesophageal reflux, dyspepsia, gastroparesis, constipation,post-operative ileus, and intestinal pseudo-obstruction; therefore, thecompounds of the subject invention can be used with a lower incidence ofside effects and toxicity.

In a further embodiment, the subject invention pertains to the breakdownproducts which are formed when the therapeutic compounds of the subjectinvention are acted upon by hydrolases. These breakdown products can beused as described herein to monitor the clearance of the therapeuticcompounds from a patient.

In yet a further embodiment, the subject invention provides methods forsynthesizing the therapeutic compounds of the subject invention.

DETAILED DISCLOSURE

The subject invention provides novel compounds which are more easilymetabolized by the metabolic drug detoxification systems. This inventionis also drawn to methods of treating disorders, such as gastroesophagealreflux disease, and related conditions. Specifically, the subjectinvention provides analogs of cisapride which have been designed to bemore susceptible to degradation by hydrolases, particularly serum and/orcytosolic esterases and methods of treatment comprising theadministration of these analogs to individuals.

Advantageously, the therapeutic compounds of the subject invention arestable in storage but have a relatively short half-life in thephysiological environment; therefore, the compounds of the subjectinvention can be used with a lower incidence of side effects andtoxicity.

In a preferred embodiment of the subject invention, therapeuticcompounds are provided which are useful in the treatment ofgastroesophageal reflux disease and which contain a moiety, such as anester group, which is susceptible to degradation by hydrolases, therebybreaking down the compound and facilitating its efficient removal fromthe treated individual. In a preferred embodiment, the therapeuticcompounds are metabolized by the Phase I drug detoxification system.

A further aspect of the subject invention pertains to the breakdownproducts which are produced when the therapeutic compounds of thesubject invention are acted upon by a hydrolase. The presence of thesebreakdown products in the urine or serum can be used to monitor the rateof clearance of the therapeutic compound from a patient.

Degradation of the compounds of the subject invention by enzymes such ashydrolases (esterases, peptidases, lipases, glycosidases, phosphateases,etc.) is particularly advantageous for drug metabolism because theseenzymes are ubiquitously distributed and their activity is not dependenton age, gender, or disease state to the same extent as oxidative hepaticdrug metabolism.

The subject invention further provides methods of treating disorders,such as gastroesophageal reflux disease comprising the administration ofa therapeutically effective amount of cisapride analogs to an individualin need of treatment. In a specific embodiment, the subject inventionprovides esterified cisapride analogs and pharmaceutical compositions ofthese esterified compounds.

The subject invention further provides materials and methods for thetreatment of emesis and such other conditions, including but not limitedto dyspepsia, gastroparesis, constipation, and intestinalpseudo-obstruction, while substantially reducing adverse effectsassociated with the administration of cisapride.

In a preferred embodiment of the subject invention, therapeuticcompounds are provided which are useful in the treatment ofgastroesophageal reflux, dyspepsia, gastroparesis, constipation,post-operative ileus, and intestinal pseudo-obstruction and whichcontain an ester group which is acted upon by esterases thereby breakingdown the compound and facilitating its efficient removal from thetreated individual.

The subject invention further provides methods of synthesizing theunique and advantageous therapeutic compounds of the subject invention.Particularly, methods of producing less toxic therapeutic agentscomprising introducing ester groups into therapeutic agents (targetdrugs) are taught. The ester linkage may be introduced into the compoundat a site which is convenient in the manufacturing process for thetarget drug. Additionally, the sensitivity of the ester linkage may bemanipulated by the addition of side groups which hinder or promote thehydrolytic activity of the hydrolases or esterases responsible forcleaving the drug at the ester locus. Methods of adding such sidegroups, as well as the side groups themselves, are well known to theskilled artisan and can be readily carried out utilizing the guidanceprovided herein.

The chemical synthesis of the disclosed analogs of cisapride can beperformed by the method described in European Patent Application No.0,076,530 A2 published Apr. 13, 1983, U.S. Pat. Nos. 4,962,115 and5,057,525 and in Van Daele et al., Drug Development Res. 8: 225-232(1986), the disclosures of which are incorporated herein by reference intheir entireties, and modified by the incorporation of an ester group ata point convenient in the synthesis of the disclosed compounds.Exemplary, non-limiting synthesis schemes for certain esterifiedcisapride analogs of the subject invention are provided below.

The present invention is concerned with novelN-(4-piperidinyl)benzamides having the general Formula (I) and theirpharmaceutically acceptable salts.

Wherein:

-   -   R₁ is H, C₁₋₄ alkyl, OH, OC₁₋₄alkyl, —COOH, —COOC₁₋₄alkyl,        —O(C═O)OC₁₋₄alkyl, —O(C═O)C₁₋₄alkyl, or —C₁₋₄alkylNR₇R₈ where R₇        and R₈ are, independently, H or C₁₋₄ alkyl;    -   R₂ is H, C₁₋₄ alkyl, —OC₁₋₄alkyl, —COOH, or —(C═O)OC₁₋₄alkyl;    -   X is O or N;    -   R₁ and X are in the cis- or trans-configuration;    -   R₃ is H or C₁₋₃ alkyl (if X is an oxygen atom, then R₃ does not        exist);    -   R₄, R₅, and R₆ are each, independently, selected from the group        consisting of hydrogen, C₁₋₄ alkyl, —OC₁₋₄ alkyl, halogen atom,        hydroxy, cyano, nitro, amino, mono- and di(lower alkyl)amino,        aminocarbonyl, arylcarbonylamino, alkylcarbonylamino,        lower-alkyl carbonyl, lower-alkyl carbonyloxy, aminosulfonyl,        lower-alkylsulfinyl, lower-alkylsulfonyl, lower-alkylthio and        mercapto; and        wherein L has the formula        —C_(n)H_(2n)—X—C_(m)H_(2m)—(CR₉R₁₀)_(p)—(C═O)O—Y, wherein    -   n is an integer from 1 to 4 inclusive;    -   X is —CH(OH)—, —NH—, —S—, —O—, or a direct bond;    -   m is an integer from 0 to 4 inclusive;    -   p is 0 or 1;    -   R₉ and R₁₀ are, independently, H, C₁₋₄ alkyl, or R₉R₁₀ are        linked and together form a 5-or a 6-membered cycloalkyl ring;        and    -   Y is H, C₁₋₁₄ alkyl or cycloalkyl optionally substituted by 1 or        more (2 to 8) heteroatoms selected from the group consisting of        O; N; S; or aryl or heteroaryl optionally substituted by 1 or        more (2 to 8) halogen atoms, C₁₋₄ alkyl, C₁₋₄alkoxy, hydroxy,        cyano, amino, alkylamino, dialkylamino, trifluoromethyl, —COOH,        or —COOC₁₋₄ alkyl (when Y is hydrogen, the compounds can also be        quaternary ammonium complexes such as tetrabutyl or        tetraethylammonium and trigonellinium).

Those skilled in the art will recognize that the structure of Formula Ihas at least 2 asymmetric centers at the 3- and 4-positions of thepiperidine ring (carbon atoms bearing the R₁ and R₂ groups).Substituents on the piperidinyl ring can have the cis- or thetrans-configuration. Accordingly, the subject invention includes the 4individual enantiomers associated with these 2 carbon centers, namelythe 3R,4R; 3S,4S; 3R,4S; and 3S,4R conformations.

Preferred compounds are those wherein R₄, R₅, and R₆ are, independently,selected from the group consisting of halo, amino, mono- anddialkylamino, and lower alkyloxy.

Particularly preferred compounds are those wherein R₄ is methoxy, R₅ isamino or methylamino, and R₅ is chloro, in the 2-, 4-, and 5-position ofthe phenyl ring, respectively.

Particularly, preferred compounds of the subject invention include thosewhere: R₁═OCH₃, R₂═H; X═O or N (if X═N, then R₃═H), R₄, R₅, and R₆ aremethoxy, amino, and chlorine at the 2, 4, and 5-position of the phenylring, respectively. R₁ and X are in the cis-configuration.

Preferred compounds within the scope of this invention have thecis-configuration.

Particularly preferred compounds of this invention have the followingformulae:

where IIIa and IIIb are mirror images of each other (enantiomers), andwhere L is defined as shown in Formula (II):

where n=1 to 4, m=0 to 4, X is a direct bond and Y is hydrogen, loweralkyl, or substituted aryl.

In the most preferred compounds, n=2, m=0, X is a direct bond, and Y ishydrogen, methyl, ethyl, isopropyl, sec-butyl, or 4-fluorophenyl.

The compounds of Formula I can generally be prepared by the reaction ofan amine of Formula (IV) with a carboxylic acid of Formula (V).

Functional derivatives of the carboxylic acids shown as Formula (V) canalso be used, as would be known to persons skilled in the art ofsynthetic chemistry. Suitable functional derivatives include acylhalides, anhydrides, and esters. The reaction conditions for mixing (IV)and (V) to produce (I) are well known conditions to the ordinary skilledsynthetic chemist.

The compounds of Formula I wherein RI is hydrogen and the substituentsin the 3- and 4-positions of the piperidine ring have the transconfiguration, said compounds being represented by the Formula (Ia), canbe prepared by reacting a 7-oxo-3-azabicyclo[4,1,0]heptane of Formula(VI) with a benzamide of Formula (VII). These compounds can be furtheralkylated in order to obtain a product wherein R₁ is other thanhydrogen.

The compounds of Formula (I) wherein the substituents in the 3- and4-positions of the piperidine ring have the cis configuration, saidcompounds being represented by the Formula (Ib), can be prepared by thereductive alkylation of a piperidone of Formula (VIII) with a benzamideof Formula (VII). This approach is applicable only when R₂ is hydrogen.Another approach, which is applicable whether R₂ is hydrogen or loweralkyl, is to react an amine of Formula (IX), having the 3- and4-substituents of the piperidine ring in the cis configuration, with acarboxylic acid of Formula (V) or a suitable functional derivativethereof (an ester, an anhydride, or an acyl chloride for example).

The compounds of this invention have therapeutic properties similar tothose of the unmodified parent compounds. Accordingly, dosage rates androutes of administration of the disclosed compounds are similar to thosealready used in the art and known to the skilled artisan (see, forexample, Physicians' Desk Reference, 54th Ed., Medical EconomicsCompany, Montvale, N.J., 2000).

The magnitude of a prophylactic or therapeutic dose of esterifiedcisapride in the acute or chronic management of diseases and/ordisorders described herein will vary with the severity of the conditionto be treated, and the route of administration. The dose, and perhapsthe dose frequency, will also vary according to the age, body weight,and response of the individual patient. In general, the total daily doserange for esterified cisapride, for the conditions described herein, isfrom about 1 mg to about 200 mg, in single or divided doses. Preferably,a daily dose range should be between about 5 mg to about 100 mg, insingle or divided doses, while most preferably, a daily dose rangeshould be between about 5 mg to about 75 mg, in single or divided doses.It is preferred that the doses are administered from 1 to 4 times a day.In managing the patient, the therapy should be initiated at a lowerdose, perhaps about 5 mg to about 10 mg, and increased up to about 50 mgor higher depending on the patient's global response. It is furtherrecommended that children, and patients over 65 years, and those withimpaired renal or hepatic function, initially receive low doses, andthat they be titrated based on individual response(s) and bloodlevel(s). It may be necessary to use dosages outside these ranges insome cases as will be apparent to those skilled in the art. Further, itis noted that the clinician or treating physician will know how and whento interrupt, adjust, or terminate therapy in conjunction withindividual patient response.

The compounds of the subject invention can be formulated according toknown methods for preparing pharmaceutically useful compositions.Formulations are described in detail in a number of sources which arewell known and readily available to those skilled in the art. Forexample, Remington's Pharmaceutical Science by E. W. Martin describesformulations which can be used in connection with the subject invention.In general, the compositions of the subject invention are formulatedsuch that an effective amount of the bioactive compound(s) is combinedwith a suitable carrier in order to facilitate effective administrationof the composition.

The compositions of the subject invention include compositions such assuspensions, solutions and elixirs; aerosols; or carriers such asstarches, sugars, microcrystalline cellulose, diluents, granulatingagents, lubricants, binders, disintegrating agents, and the like, in thecase of oral solid preparations (such as powders, capsules, and tablets)with the oral solid preparations being preferred over the oral liquidpreparations. A preferred oral solid preparation is capsules. The mostpreferred oral solid preparation is tablets. Preferred amounts of activeingredient (i.e., an esterified cisapride analog) in a solid dosage formare about 5 mg, 10 mg, and 25 mg.

Further, acceptable carriers can be either solid or liquid. Solid formpreparations include powders, tablets, pills, capsules, cachets,suppositories and dispersible granules. A solid carrier can be one ormore substances which may act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, preservatives,tablet disintegrating agents or encapsulating materials.

The disclosed pharmaceutical compositions may be subdivided into unitdoses containing appropriate quantities of the active component. Theunit dosage form can be a packaged preparation, such as packetedtablets, capsules, and powders in paper or plastic containers or invials or ampules. Also, the unit dosage can be a liquid basedpreparation or formulated to be incorporated into solid food products,chewing gum, or lozenge.

In addition to the common dosage forms set out above, the compounds ofthe present invention may also be administered by controlled releasemeans and/or delivery devices such as those described in U.S. Pat. Nos.:3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, thedisclosures of which are hereby incorporated by reference in theirentirety.

Any suitable route of administration may be employed for providing thepatient with an effective dosage of esterified cisapride. For example,oral, rectal, parenteral (subcutaneous, intramuscular, intravenous),transdermal, and like forms of administration may be employed. Dosageforms include tablets, troches, dispersions, suspensions, solutions,capsules, patches, and the like.

One embodiment of the invention provides a method of treatinggastroesophageal reflux disease in a mammal, while substantiallyreducing the concomitant adverse effects associated with theadministration of cisapride, which comprises administering to a human inneed of such treatment, a therapeutically effective amount of esterifiedcisapride, or a pharmaceutically acceptable salt thereof. A preferredembodiment is the treatment of gastroesophageal reflux disease inhumans.

Another embodiment of the invention provides a composition for thetreatment of a human suffering from gastroesophageal reflux disease,which comprises a therapeutically effective amount of esterifiedcisapride, or a pharmaceutically acceptable salt thereof.

Yet another embodiment of the present invention provides a method ofeliciting an anti-emetic effect in a mammal, while substantiallyreducing the adverse effects associated with the administration ofcisapride, which comprises administering to a mammal in need of suchanti-emetic therapy, a therapeutically effective amount of esterifiedcisapride, or a pharmaceutically acceptable salt thereof. Preferably,the mammal is a human.

In an additional embodiment, the present invention encompasses ananti-emetic composition for the treatment of a mammal in need ofanti-emetic therapy, which comprises a therapeutically effective amountof esterified cisapride, or a pharmaceutically acceptable salt thereof.

A further aspect of the present invention includes a method of treatinga condition caused by gastrointestinal motility dysfunction in a mammalwhich comprises administering to a mammal in need of treatment forgastrointestinal motility dysfunction, a therapeutically effectiveamount of esterified cisapride, or a pharmaceutically acceptable saltthereof. Conditions caused by gastrointestinal motility dysfunctioninclude, but are not limited to, dyspepsia, gastroparesis, constipation,post-operative ileus, and intestinal pseudo-obstruction. Preferably, themammal is a human.

The observation that cisapride enters the central nervous system andbinds to 5HT4 receptors indicates that cisapride may havecentrally-mediated effects. Cisapride is a potent ligand at 5HT4receptors, and these receptors are located in several areas of thecentral nervous system. Modulation of serotonergic systems has a varietyof behavioral effects. According, the compounds of the subject inventioncan be used in the treatment of: 1) cognitive disorders, including butnot limited to Alzheimer's disease; 2) behavioral disorders, includingbut not limited to schizophrenia, mania, obsessive-compulsive disorder,and psychoactive substance use disorders; 3) mood disorders, includingbut not limited to depression and anxiety; and 4) disorders of controlof autonomic function, including but not limited to essentialhypertension and sleep disorders.

Accordingly, the present invention also provides methods of treatingcognitive, behavioral, mood, or autonomic function control disorders ina mammal comprising the administration of a therapeutically effectiveamount of esterified cisapride, or a pharmaceutically acceptable saltthereof. Preferably, the mammal is a human.

The term “pharmaceutically acceptable salts” or “a pharmaceuticallyacceptable salt thereof” refer to salts prepared from pharmaceuticallyacceptable non-toxic acids or bases including inorganic acids and basesand organic acids and bases. Since the compound of the present inventionis basic, salts may be prepared from pharmaceutically acceptablenon-toxic acids. Suitable pharmaceutically acceptable acid additionsalts for the compound of the present invention include acetic,benzenesulfonic (besylate), benzoic, camphorsulfonic, citric,ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaricacid, p-toluenesulfonic, and the like. Preferred acid addition salts arethe chloride and sulfate salts. In the most preferred embodiment,esterified cisapride analogs are administered as the free base.

The term “therapeutically effective amount” means: 1) an amountsufficient to alleviate reflux disease, 2) an amount sufficient toalleviate nausea and vomiting, or 3) an amount sufficient to alleviate acondition caused by gastrointestinal motility dysfunction.Therapeutically effective amounts of esterified cisapride areencompassed by the above-described dosage amounts and dose frequencyschedule.

A “mammal” may be, for example, a mouse, rat, pig, horse, rabbit, goat,pig, cow, cat, dog, or human. In a preferred embodiment, the mammal is ahuman.

The term “individual(s)” is defined as a single mammal to which isadministered a compound of the present invention. The mammal may be arodent, for example a mouse or rat, pig, horse, rabbit, goat, pig, cow,cat, dog, or human. In a preferred embodiment, the individual is ahuman.

The term “esterified cisapride” means therapeutic compounds of thesubject invention which contain an ester group which does not detractfrom the ability of these compounds to provide a therapeutic benefit,but which makes these compounds more susceptible to degradation byhydrolases, particularly serum and/or cytosolic esterases, and whichreduces the interaction of the cytochrome P-450 drug detoxificationsystem with the cisapride compounds. Esterase mediated metabolism of theesterified cisapride compounds reduces the role of the cytochrome P-450drug detoxification system in cisapride metabolism and reduces oreliminates adverse effects caused by cisapride.

The term “adverse effects” includes, but is not limited to,gastrointestinal disorders such as diarrhea, abdominal cramping, andabdominal grumbling; tiredness; headache; increased systolic pressure;death; ventricular tachycardia; ventricular fibrillation; torsades depointes; QT prolongation; increased heart rate; neurological and CNSdisorders; and interaction of cisapride with other drugs givenconcurrently such as digoxin, diazepam, ethanol, acenocoumarol,cimetidine, ranitidine, paracetamol, and propranolol.

The term “gastroesophageal reflux disease” as used herein means theincidence of, and the symptoms of, those conditions causing the backwardflow of the stomach contents into the esophagus.

The terms “eliciting an anti-emetic effect” and “anti-emetic therapy” asused herein mean providing relief from or preventing the symptoms ofnausea and vomiting induced spontaneously or associated with emetogeniccancer chemotherapy or irradiation therapy.

The term “treating a condition caused by gastrointestinal motilitydysfunction” as used herein means treating the symptoms and conditionsassociated with this disorder which include, but are not limited to,dyspepsia, gastroparesis, constipation, post-operative ileus, andintestinal pseudo-obstruction.

The term “prokinetic” as used herein means the enhancement ofperistalsis in, and thus the movement through the gastrointestinaltract.

The term “dyspepsia” as used herein means a condition characterized byan impairment of the power or function of digestion that can arise as asymptom of a primary gastrointestinal dysfunction or as a complicationdue to other disorders such as appendicitis, gallbladder disturbances,or malnutrition.

The term “gastroparesis” as used herein means a paralysis of the stomachbrought about by a motor abnormality in the stomach or as a complicationof diseases such as diabetes, progressive systemic sclerosis, anorexianervosa, or myotonic dystrophy.

The term “constipation” as used herein means a condition characterizedby infrequent or difficult evacuation of feces resulting from conditionssuch as lack of intestinal muscle tone or intestinal spasticity.

The term “post-operative ileus” as used herein means an obstruction inthe intestine due to a disruption in muscle tone following surgery.

The term “intestinal pseudo-obstruction” as used herein means acondition characterized by constipation, colicky pain, and vomiting, butwithout evidence of physical obstruction.

All patents, patent applications, provisional applications, andpublications referred to or cited herein are incorporated by referencein their entirety to the extent they are not inconsistent with theexplicit teachings of this specification.

Following is an example which illustrates procedures for practicing theinvention. This example should not be construed as limiting. Allpercentages are by weight and all solvent mixture proportions are byvolume unless otherwise noted.

EXAMPLE 1 Synthesis of Specific Compounds of the Subject Invention

Preferred compounds of the subject invention have the Formula (Ib) wherethe substituents at the 3- and 4-positions of the piperidine ring havethe cis-configuration, R₁ is methoxy, R₂ is hydrogen, R₄ is methoxy, R₅is amino, R₆ is chloro in the 2-, 4-, and 5-positions of the benzamidering, respectively. In particularly preferred compounds, L has theFormula (II) wherein n=2, m=0, X is a direct bond, and Y is hydrogen,methyl, ethyl, isopropyl, sec-butyl, or 4-fluorophenyl. The commonintermediate to these preferred compounds is compound 9 as describedbelow.

The synthesis can be described in more details as follows:

1-carbethoxy-4-piperidone 1 reacts with bromine in an inert solvent suchas dichloromethane to give high yields of1-carbethoxy-3-bromo-4-piperidone 2. The bromo compound 2 reacts withsodium methoxide in methanol to give1-carbethoxy-3-hydroxy-4,4-dimethoxypiperidine 3, which in turn isalkylated to the corresponding 3-methoxy analog 4 with iodomethane indimethylformamide in the presence of sodium hydride. The ketal 4 ishydrolyzed to 1-carbethoxy-3-methoxy-4-piperidone 5 by stirring in 1%sulfuric acid at room temperature. The amine 6 of cis-configuration isthen readily obtained by reductive alkylation of 5 with benzylamine inthe presence of hydrogen gas and 10% Pd/C with a small amount ofthiophene. Further hydrogenolysis of the benzyl moiety with Pd/C and nothiophene gives the primary amine 7. Compound 7 in turn reacts with thecommercially available 4-amino-5-chloro-2-methoxybenzoic acid in thepresence of DCC and dimethyaminopyridine in dichloromethane to give thebenzamide 8. Compound 8 is then hydrolyzed to the intermediate 9 withpotassium hydroxide in ethanol/water.

The intermediate 2 reacts with acrylic acid or an ester thereof in thepresence of a base such as diethylamine to give the final compounds 11(see diagram below).

The intermediate 9 reacts with acrylic acid or an ester thereof in thepresence of a base such as diethylamine to give the final compounds 11(see diagram below).

For example: Acryloyl chloride and 4-fluorophenol react indichloromethane in the presence of triethylamine to give 4-fluorophenylacrylate 10 (R=4-fluorophenyl). Compound 10 is then added to a solutionof 9 in ethanol and diethylamine to give 11 (R=4-fluorophenyl) afterusual workup.

EXAMPLE 2 Additional Synthesis Protocols

In addition to the general synthetic methods described above, thefollowing procedures can also be utilized:

The compounds of Formula (I) wherein X is oxygen and R₁ is methoxy canbe prepared by reduction of a compound of Formula (VIII) with sodiumborohydride in lower alkanol solvent, followed by coupling of theresulting alcohol (X) with a substituted benzoic acid of Formula (V) inthe presence of a coupling reagent such as a dialkylcarbodiimide.

Compounds of Formula I where L is CH₂CHMeCOOR can be prepared byreacting the amine intermediate IX with methacrylic acid or an esterthereof, optionally in the presence of a base such as Triton B ortriethylamine.

Compounds of Formula I where L is CH₂CMe₂COOR can be prepared accordingto Katritzky et al., Synthesis (1989), 747 by reacting thebenzotriazolylmethyl derivative of the amine intermediate IX with a2-bromoisobutyric acid ester in the presence of zinc and trimethylsilylchloride.

Compounds of Formula I where L is CH₂COOR are prepared by alkylatingintermediate IX with bromoacetic acid or an ester thereof in thepresence of a base such as potassium carbonate or triethylamine in aninert solvent such as tetrahydrofuran or dimethylformamide.

Compounds of Formula I where L is (CH₂)₃COOR can be made by alkylatingintermediate IX with 4-bromobutyric acid or an ester thereof in thepresence of a base such as potassium carbonate or triethylamine in aninert solvent such as tetrahydrofuran or dimethylformamide.

EXAMPLE 3 Additional Synthesis Procedures

3-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-propionicAcid

A solution of4-amino-5-chloro-2-methoxy-N-(3-methoxy-piperidin-4-yl)-benzamide (1 g,3.2 mmol), and 241 μL of acrylic acid in 50 ml dichloromethane wasstirred under nitrogen for 6 hr then concentrated in vacuo. The residuewas slurried with hot ethyl acetate and filtered at room temperature toyield 1.15 g of product as a white solid. Substituting Methacrylic Acidfor Acrylic Acid Provided:3-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-2-methyl-propionicAcid

EXAMPLE 4 Additional Synthesis Procedures

3-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-propionicAcid Methyl Ester

A solution of 640 mg of3-[4-(4-Amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-propionicacid in 20 ml methanol was treated with 1 ml sulfuric acid and heated atreflux under argon for 3 hr. The mixture was diluted with sodiumcarbonate solution, extracted into dichloromethane dried over sodiumsulfate, and concentrated in vacuo to provide 600 mg of crude ester asan oil. Trituration with methanol/ethyl acetate afforded a crystallinesolid.The following compounds can be similarly prepared:3-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-propionicacid ethyl ester3-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-propionicacid isopropyl ester3-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-propionicacid 2-methoxy-ethyl ester3-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-propionicacid cyclohexyl ester3-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-2-methyl-propionicacid ethyl ester3-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-2-methyl-propionicacid isopropyl ester3-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-2-methyl-propionicacid 2-methoxy-ethyl ester3-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-2-methyl-propionicacid cyclohexyl ester

EXAMPLE 5 Additional Synthesis Procedure

[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-aceticAcid Methyl Ester

A mixture containing 313 mg norcisapride and 276 mg potassium carbonatein 10 ml DMF was treated with 153 mg of bromo-acetic acid methyl ester.The reaction was stirred at ambient temperature for 8 hr. Extractiveworkup with waterdichloromethane followed by flash chromatographyafforded 455 mg of product.The following compounds can be similarly prepared:[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-aceticacid phenyl ester[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-aceticacid 4-fluoro-benzyl ester

EXAMPLE 6 Additional Synthesis Procedures

4-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-butricAcid Ethyl Ester

A mixture containing 313 mg norcisapride, 276 mg potassium carbonate,and a pinch of sodium iodide in 10 ml DMF was treated with 195 mg4-bromo-butyric acid ethyl ester. The reaction was stiffed at ambienttemperature for 14 hr. Extractive workup with water/dichioromethanefollowed by flash chromatography afforded 230 mg of product.

The following compounds can be similarly prepared:

[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-butyricacid phenyl ester

[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-butyricacid 4-fluoro-benzyl ester

EXAMPLE 7 Activity Assay

A segment of oesophagus obtained from Wistar derived male or female ratsweighing 270±25 g and sacrificed by CO₂ overexposure is used. The tissueis placed under 1 g tension in a 10 mL bath containing 3 μM indomethacinand 1 μM ketanserin in Krebs solution pH 7.4 and at 32° C. andsubmaximal tonic isometrically recorded contraction is induced bycarbachol (1 μM). Test substance (30 μM)-induced relaxation by 50percent or more (≧50%) within 5 min, relative to control 0.3 μMserotonin (5-HT) response, indicates possible receptor agonist activity.

At a test substance concentration where no significant agonist activityis seen, ability to reduce the serotonin-induced relaxatant response by50 percent or more (≧50%) indicates receptor antagonist activity.

It should be understood that the examples and embodiments describedherein are for illustrative purposes only and that various modificationsor changes in light thereof will be suggested to persons skilled in theart and are to be included within the spirit and purview of thisapplication and the scope of the appended claims. Further, all patents,patent applications, provisional applications, and publications referredto or cited herein are incorporated by reference in their entirety tothe extent they are not inconsistent with the explicit teachings of thisspecification.

1. A method for treating a disease state by stimulating the motility ofthe gastrointestinal system, and wherein said disease state is selectedfrom the group consisting of gastroesophageal reflux disease, dyspepsia,gastroparesis, constipation, post-operative ileus, and intestinalpseudo-obstruction, wherein said method comprises administering, to anindividual in need of such a treatment, a compound, or an analog or saltthereof, wherein said compound has the following structure:

wherein: R₁ is H, C₁₋₄ alkyl, OH, OC₁₋₄alkyl, —COOH, —COOC₁₋₄alkyl,—O(C═O)OC₁₋₄alkyl, —O(C═O)C₁₋₄alkyl, or —C₁₋₄alkylNR₇R₈ where R₇ and R₈are, independently, H or C₁₋₄ alkyl; R₂ is H, C₁₋₄ alkyl, —OC₁₋₄alkyl,—COOH, or —(C═O)OC₁₋₄alkyl; X is O or N; R₃ is H or C₁₋₃ alkyl (if X isan oxygen atom, then R₃ does not exist); R₄, R₅, and R₆ are each,independently, selected from the group consisting of hydrogen, C₁₋₄alkyl, —OC₁₋₄ alkyl, halogen atom, hydroxy, cyano, nitro, amino, mono-and di(lower alkyl)amino, aminocarbonyl, arylcarbonylamino,alkylcarbonylamino, lower-alkyl carbonyl, lower-alkyl carbonyloxy,aminosulfonyl, lower-alkylsulfinyl, lower-alkylsulfonyl, lower-alkylthioand mercapto; and wherein L has the formula—C_(n)H_(2n)X—C_(m)H_(2m)—(CR₉R₁₀)_(p)—(C═O)O—Y, wherein n is an integerfrom 1 to 4 inclusive; X is —CH(OH)—, —NH—, —S—, —O—, or a direct bond;m is an integer from 0 to 4 inclusive; p is 0 or 1; R₉ and R₁₀ are,independently, H, C₁₋₄ alkyl, or R₉R₁₀ are linked and together form a 5-or a 6-membered cycloalkyl ring; and Y is cycloalkyl optionallysubstituted by 1 or more heteroatoms selected from the group consistingof O; N; S; or aryl or heteroaryl optionally substituted by 1 or morehalogen atoms, C₁₋₄ alkyl, C₁₋₄alkoxy, hydroxy, cyano, amino,alkylamino, dialkylamino, trifluoromethyl, —COOH, or —COOC₁₋₄alkyl. 2.The method, according to claim 1, wherein said disease state is selectedfrom the group consisting of gastroesophageal reflux disease, dyspepsia,gastroparesis, constipation, and post-operative ileus, and intestinalpseudo-obstruction.
 3. The method, according to claim 2, wherein saiddisease state is gastroesophageal reflux disease.
 4. The method,according to claim 1, wherein said individual is a human.
 5. The method,according to claim 1, wherein R₄, R₅, and R₆ are, independently,selected from the group consisting of halo, amino, mono- anddialkylamino, and lower alkyloxy.
 6. The method, according to claim 1,wherein R₄ is methoxy, R₅ is amino or methylamino, and R₆ is chloro, inthe 2-, 4-, and 5-position of the phenyl ring, respectively.
 7. Themethod, according to claim 1, wherein said compound is selected from thegroup consisting of:

where IIIa and IIIb are mirror images of each other (enantiomers), andwhere L is defined as shown in Formula (II):

where n=1 to 4, m=0 to 4, X is a direct bond and Y is hydrogen, loweralkyl, or substituted aryl.
 8. The method, according to claim 1, whereinR₁═OCH₃, R₂═H; X═O or N (if X═N, then R₃═H); R₄, R₅, and R₆ are methoxy,amino, and chlorine at the 2, 4, and 5-position of the phenyl ring,respectively.
 9. The method, according to claim 1, wherein bothasymmetric centers are in the cis-configuration.
 10. A pharmaceuticalcomposition comprising a therapeutically-effective amount of a compound,or a salt thereof, wherein said compound has the following structure:

wherein: R₁ is H, C₁₋₄ alkyl, OH, OC₁₋₄alkyl, —COOH, —COOC₁₋₄alkyl,—O(C═O)OC₁₋₄alkyl, —O(C═O)C₁₋₄alkyl, or —C₁₋₄alkylNR₇R₈ where R₇ and R₈are, independently, H or C₁₋₄ alkyl; R₂ is H, C₁₋₄ alkyl, —OC₁₋₄alkyl,—COOH, or —(C═O)OC₁₋₄alkyl; X is O or N; R₃ is H or C₁₋₃ alkyl (if X isan oxygen atom, then R₃ does not exist); R₄, R₅, and R₆ are each,independently, selected from the group consisting of hydrogen, C₁₋₄alkyl, —OC₁₋₄ alkyl, halogen atom, hydroxy, cyano, nitro, amino, mono-and di(lower alkyl)amino, aminocarbonyl, arylcarbonylamino,alkylcarbonylamino, lower-alkyl carbonyl, lower-alkyl carbonyloxy,aminosulfonyl, lower-alkylsulfinyl, lower-alkylsulfonyl, lower-alkylthioand mercapto; and wherein L has the formula—C_(n)H_(2n)—X—C_(m)H_(2m)—(CR₉R₁₀)_(p)—(C═O)O—Y, wherein n is aninteger from 1 to 4 inclusive; X is —CH(OH)—, —NH—, —S—, —O—, or adirect bond; m is an integer from 0 to 4 inclusive; p is 0 or 1; R₉ andR₁₀ are, independently, H, C₁₋₄ alkyl, or R₉R₁₀ are linked and togetherform a 5- or a 6-membered cycloalkyl ring; and Y is cycloalkyloptionally substituted by 1 or more heteroatoms selected from the groupconsisting of O; N; S; or aryl or heteroaryl optionally substituted by 1or more halogen atoms, C₁₋₄ alkyl, C₁₋₄alkoxy, hydroxy, cyano, amino,alkylamino, dialkylamino, trifluoromethyl, —COOH, or —COOC₁₋₄alkyl. 11.The pharmaceutical composition, according to claim 10, wherein R₄, R₅,and R₆ are, independently, selected from the group consisting of halo,amino, mono- and dialkylamino, and lower alkyloxy.
 12. Thepharmaceutical composition, according to claim 10, wherein R₄ ismethoxy, R₅ is amino or methylamino, and R₆ is chloro, in the 2-, 4-,and 5-position of the phenyl ring, respectively.
 13. The pharmaceuticalcomposition, according to claim 10, wherein said compound is selectedfrom the group consisting of:

where IIIa and IIIb are mirror images of each other (enantiomers), andwhere L is defined as shown in Formula (II):

where n=1 to 4, m=0 to 4, X is a direct bond and Y is hydrogen, loweralkyl, or substituted aryl.
 14. The pharmaceutical composition,according to claim 10, wherein R₁═OCH₃, R₂═H; X═O or N (if X═N, thenR₃═H), R₄, R₅, and R₆ are methoxy, amino, and chlorine at the 2, 4, and5-position of the phenyl ring, respectively.
 15. The pharmaceuticalcomposition, according to claim 10, wherein both asymmetric centers arein the cis-configuration.
 16. A compound, or salt thereof, wherein saidcompound has the following structure:

wherein: R₁ is H, C₁₋₄ alkyl, OH, OC₁₋₄alkyl, —COOH, —COOC₁₋₄alkyl,—O(C═O)OC₁₋₄alkyl, —O(C═O)C₁₋₄alkyl, or —C₁₋₄alkylNR₇R₈ where R₇ and R₈are, independently, H or C₁₋₄ alkyl; R₂ is H, C₁₋₄ alkyl, —OC₁₋₄alkyl,—COOH, or —(C═O)OC₁₋₄alkyl; X is O or N; R₃ is H or C₁₋₃ alkyl (if X isan oxygen atom, then R₃ does not exist); R₄, R₅, and R₆ are each,independently, selected from the group consisting of hydrogen, C₁₋₄alkyl, —OC₁₋₄ alkyl, halogen atom, hydroxy, cyano, nitro, amino, mono-and di(lower alkyl)amino, aminocarbonyl, arylcarbonylamino,alkylcarbonylamino, lower-alkyl carbonyl, lower-alkyl carbonyloxy,aminosulfonyl, lower-alkylsulfinyl, lower-alkylsulfonyl, lower-alkylthioand mercapto; and wherein L has the formula—C_(n)H_(2n)—XC_(m)H_(2m)—(CR₉R₁₀)_(p)—(C═O)O—Y, wherein n is an integerfrom 1 to 4 inclusive; X is —CH(OH)—, —NH—, —S—, —O—, or a direct bond;m is an integer from 0 to 4 inclusive; p is 0 or 1; R₉ and R₁₀ are,independently, H, C₁₋₄ alkyl, or R₉R₁₀ are linked and together form a 5-or a 6-membered cycloalkyl ring; and Y is cycloalkyl optionallysubstituted by 1 or more heteroatoms selected from the group consistingof O; N; S; or aryl or heteroaryl optionally substituted by 1 or morehalogen atoms, C₁₋₄ alkyl, C₁₋₄alkoxy, hydroxy, cyano, amino,alkylamino, dialkylamino, trifluoromethyl, —COOH, or —COOC₁₋₄alkyl. 17.The compound, according to claim 16, wherein R₄, R₅, and R₆ are,independently, selected from the group consisting of halo, amino, mono-and dialkylamino, and lower alkyloxy.
 18. The compound, according toclaim 16, wherein R₄ is methoxy, R₅ is amino or methylamino, and R₆ ischloro, in the 2-, 4-, and 5-position of the phenyl ring, respectively.19. The compound, according to claim 16, wherein said compound isselected from the group consisting of:

where IIIa and IIIb are mirror images of each other (enantiomers), andwhere L is defined as shown in Formula (II):

where n=1 to 4, m=0 to 4, X is a direct bond and Y is hydrogen, loweralkyl, or substituted aryl.
 20. The compound, according to claim 16,wherein R₁═OCH₃, R₂═H; X═O or N (if X═N, then R₃═H); R₄, R₅, and R₆ aremethoxy, amino, and chlorine at the 2, 4, and 5-position of the phenylring, respectively.
 21. The compound, according to claim 16, whereinboth asymmetric centers are in the cis-configuration.
 22. A method fortreating a condition selected from the group consisting of 1) cognitivedisorders, 2) behavioral disorders, 3) mood disorders, and 4) disordersof control of autonomic function wherein said method comprisesadministering to an individual in need of such treatment, an effectiveamount of a compound, or an analog or salt thereof, wherein saidcompound has the following structure:

wherein: R₁ is H, C₁₋₄ alkyl, OH, OC₁₋₄alkyl, —COOH, —COOC₁₋₄alkyl,—O(C═O)OC₁₋₄alkyl, —O(C═O)C₁₋₄alkyl, or —C₁₋₄alkylNR₇R₈ where R₇ and R₈are, independently, H or C₁₋₄ alkyl; R₂ is H, C₁₋₄ alkyl, —OC₁₋₄alkyl,—COOH, or —(C═O)OC₁₋₄alkyl; X is O or N; R₃ is H or C₁₋₃ alkyl (if X isan oxygen atom, then R₃ does not exist); R₄, R₅, and R₆ are each,independently, selected from the group consisting of hydrogen, C₁₋₄alkyl, —OC₁₋₄ alkyl, halogen atom, hydroxy, cyano, nitro, amino, mono-and di(lower alkyl)amino, aminocarbonyl, arylcarbonylamino,alkylcarbonylamino, lower-alkyl carbonyl, lower-alkyl carbonyloxy,aminosulfonyl, lower-alkylsulfinyl, lower-alkylsulfonyl, lower-alkylthioand mercapto; and wherein L has the formula—C_(n)H_(2n)—X—C_(m)H_(2m)—(CR₉R₁₀)_(p)—(C═O)O—Y, wherein n is aninteger from 1 to 4 inclusive; X is —CH(OH)—, —NH—, —S—, —O—, or adirect bond; m is an integer from 0 to 4 inclusive; p is 0 or 1; R₉ andR₁₀ are, independently, H, C₁₋₄ alkyl, or R₉R₁₀ are linked and togetherform a 5- or a 6-membered cycloalkyl ring; and Y is cycloalkyloptionally substituted by 1 or more heteroatoms selected from the groupconsisting of O; N; S; or aryl or heteroaryl optionally substituted by 1or more halogen atoms, C₁₋₄ alkyl, C₁₋₄alkoxy, hydroxy, cyano, amino,alkylamino, dialkylamino, trifluoromethyl, —COOH, or —COOC₁₋₄alkyl. 23.The method, according to claim 22, wherein said cognitive disorder isAlzheimer's disease.
 24. The method, according to claim 22, wherein saidbehavioral disorder is selected from the group consisting ofschizophrenia, mania, obsessive-compulsive disorder, and psychoactivesubstance use disorders.
 25. The method, according to claim 22, whereinsaid mood disorder is selected from the group consisting of depressionand anxiety.
 26. The method, according to claim 22, wherein said mooddisorder is selected from the group consisting of depression andanxiety.
 27. The method, according to claim 22, wherein said disorder ofcontrol of autonomic function is selected from the group consisting ofessential hypertension and sleep disorders.
 28. The method, according toclaim 22, wherein said individual is a human.
 29. The method, accordingto claim 22, wherein R₄, R₅, and R₆ are, independently, selected fromthe group consisting of halo, amino, mono- and dialkylamino, and loweralkyloxy.
 30. The method, according to claim 22, wherein R₄ is methoxy,R₅ is amino or methylamino, and R₆ is chloro, in the 2-, 4-, and5-position of the phenyl ring, respectively.
 31. The method, accordingto claim 22, wherein said compound is selected from the group consistingof:

where IIIa and IIIb are mirror images of each other (enantiomers), andwhere L is defined as shown in Formula (II):

where n=1 to 4, m=0 to 4, X is a direct bond and Y is hydrogen, loweralkyl, or substituted aryl.
 32. The method, according to claim 22,wherein R₁═OCH₃; R₂═H; X═O or N (if X═N, then R₃═H), R₄, R₅, and R₆ aremethoxy, amino, and chlorine at the 2, 4, and 5-position of the phenylring, respectively.
 33. The method, according to claim 22, wherein bothasymmetric centers are in the cis-configuration.